Human African trypanosomiasis : current status and eradication efforts

Epidemics of human African trypanosomiasis (HAT) in the 20th century led to millions of deaths. However, since the start of the twenty-first century, there is been a continued decline in the number of reported cases, due to increased investment and prioritisation of control efforts. Systematic screening of at-risk areas and widespread access to increasingly advanced diagnostics and treatments, along with much improved vector control, have all helped to make disease elimination achievable in the near future. Despite the progress, the danger of disease resurgence is well-known for HAT and continued surveillance and treatment availability is essential. Additionally, many uncertainties regarding HAT transmission remain and combine to make potential disease eradication a complete unknown

Disentangling the influence of livestock vs. farm density on livestock disease epidemics

Susceptible host density is a key factor that influences the success of invading pathogens. However, for diseases affecting livestock, there are two aspects of host density: livestock and farm density, which are seldom considered independently. Traditional approaches of simulating disease outbreaks on real‐world farm data make dissecting the relative importance of farm and livestock density difficult owing to their inherent correlation in many farming regions. We took steps to disentangle these densities and study their relative influences on epidemic size by simulating foot‐and‐mouth disease outbreaks on factorial combinations of cattle and farm populations in artificial county areas, resulting in 50 unique cattle/farm density combinations. In these simulations, increasing cattle density always resulted in larger epidemics, regardless of farm density. Alternatively, increasing farm density only led to larger epidemics in scenarios of high cattle density. We compared these results with simulations performed on real‐world farm data from the United States, where we initiated outbreaks in U.S. counties that varied in county‐level cattle density and farm density. We found a similar, but weaker relationship between cattle density and epidemic size in the U.S. simulations. We tested the sensitivity of these outcomes to variation in pathogen dispersal and farm‐level susceptibility model parameters and found that although variation in these parameters quantitatively influenced the size of the epidemic, they did not qualitatively change the relative influence of cattle vs. farm density in factorial simulations. By reducing the correlation between farm and livestock density in factorial simulations, we were able to clearly demonstrate the increase in epidemic size that occurred as farm sizes grew larger (i.e., through increasing county‐level cattle populations), across levels of farm density. These results suggest livestock production trends in many industrialized countries that concentrate livestock on fewer, but larger farms have the potential to facilitate larger livestock epidemics

Village-scale persistence and elimination of gambiense human African trypanosomiasis

Gambiense human African trypanosomiasis (gHAT) is one of several neglected tropical diseases that is targeted for elimination by the World Health Organization. Recent years have seen a substantial decline in the number of globally reported cases, largely driven by an intensive process of screening and treatment. However, this infection is highly focal, continuing to persist at low prevalence even in small populations. Regional elimination, and ultimately global eradication, rests on understanding the dynamics and persistence of this infection at the local population scale. Here we develop a stochastic model of gHAT dynamics, which is underpinned by screening and reporting data from one of the highest gHAT incidence regions, Kwilu Province, in the Democratic Republic of Congo. We use this model to explore the persistence of gHAT in villages of different population sizes and subject to different patterns of screening. Our models demonstrate that infection is expected to persist for long periods even in relatively small isolated populations. We further use the model to assess the risk of recrudescence following local elimination and consider how failing to detect cases during active screening events informs the probability of elimination. These quantitative results provide insights for public health policy in the region, particularly highlighting the difficulties in achieving and measuring the 2030 elimination goal

Insights from quantitative and mathematical modelling on the proposed 2030 goal for gambiense human African trypanosomiasis (gHAT)

Gambiense human African trypanosomiasis (gHAT) is a parasitic, vector-borne neglected tropical disease that has historically affected populations across West and Central Africa and can result in death if untreated. Following from the success of recent intervention programmes against gHAT, the World Health Organization (WHO) has defined a 2030 goal of global elimination of transmission (EOT). The key proposed indicator to measure achievement of the goal is to have zero reported cases. Results of previous mathematical modelling and quantitative analyses are brought together to explore both the implications of the proposed indicator and the feasibility of achieving the WHO goal. Whilst the indicator of zero case reporting is clear and measurable, it is an imperfect proxy for EOT and could arise either before or after EOT is achieved. Lagging reporting of infection and imperfect diagnostic specificity could result in case reporting after EOT, whereas the converse could be true due to underreporting, lack of coverage, and cryptic human and animal reservoirs. At the village-scale, the WHO recommendation of continuing active screening until there are three years of zero cases yields a high probability of local EOT, but extrapolating this result to larger spatial scales is complex. Predictive modelling of gHAT has consistently found that EOT by 2030 is unlikely across key endemic regions if current medical-only strategies are not bolstered by improved coverage, reduced time to detection and/or complementary vector control. Unfortunately, projected costs for strategies expected to meet EOT are high in the short term and strategies that are cost-effective in reducing burden are unlikely to result in EOT by 2030. Future modelling work should aim to provide predictions while taking into account uncertainties in stochastic dynamics and infection reservoirs, as well as assessment of multiple spatial scales, reactive strategies, and measurable proxies of EOT

A Lack of Parasitic Reduction in the Obligate Parasitic Green Alga \u3cem\u3eHelicosporidium\u3c/em\u3e

The evolution of an obligate parasitic lifestyle is often associated with genomic reduction, in particular with the loss of functions associated with increasing host-dependence. This is evident in many parasites, but perhaps the most extreme transitions are from free-living autotrophic algae to obligate parasites. The best-known examples of this are the apicomplexans such as Plasmodium, which evolved from algae with red secondary plastids. However, an analogous transition also took place independently in the Helicosporidia, where an obligate parasite of animals with an intracellular infection mechanism evolved from algae with green primary plastids. We characterised the nuclear genome of Helicosporidium to compare its transition to parasitism with that of apicomplexans. The Helicosporidium genome is small and compact, even by comparison with the relatively small genomes of the closely related green algae Chlorella and Coccomyxa, but at the functional level we find almost no evidence for reduction. Nearly all ancestral metabolic functions are retained, with the single major exception of photosynthesis, and even here reduction is not complete. The great majority of genes for light-harvesting complexes, photosystems, and pigment biosynthesis have been lost, but those for other photosynthesis-related functions, such as Calvin cycle, are retained. Rather than loss of whole function categories, the predominant reductive force in the Helicosporidium genome is a contraction of gene family complexity, but even here most losses affect families associated with genome maintenance and expression, not functions associated with host-dependence. Other gene families appear to have expanded in response to parasitism, in particular chitinases, including those predicted to digest the chitinous barriers of the insect host or remodel the cell wall of Helicosporidium. Overall, the Helicosporidium genome presents a fascinating picture of the early stages of a transition from free-living autotroph to parasitic heterotroph where host-independence has been unexpectedly preserved

Functional genomics of mountain pine beetle (Dendroctonus ponderosae) midguts and fat bodies

<p>Abstract</p> <p>Background</p> <p>The mountain pine beetle (<it>Dendroctonus ponderosae</it>) is a significant coniferous forest pest in western North America. It relies on aggregation pheromones to colonize hosts. Its three major pheromone components, <it>trans</it>-verbenol, <it>exo</it>-brevicomin, and frontalin, are thought to arise via different metabolic pathways, but the enzymes involved have not been identified or characterized. We produced ESTs from male and female midguts and associated fat bodies and used custom oligonucleotide microarrays to study gene expression patterns and thereby made preliminary identification of pheromone-biosynthetic genes.</p> <p>Results</p> <p>Clones from two un-normalized cDNA libraries were directionally sequenced from the 5' end to yield 11,775 ESTs following sequence cleansing. The average read length was 550 nt. The ESTs clustered into 1,201 contigs and 2,833 singlets (4,034 tentative unique genes). The ESTs are broadly distributed among GO functional groups, suggesting they reflect a broad spectrum of the transcriptome. Among the most represented genes are representatives of sugar-digesting enzymes and members of an apparently Scolytid-specific gene family of unknown function. Custom NimbleGen 4-plex arrays representing the 4,034 tentative unique genes were queried with RNA from eleven different biological states representing larvae, pupae, and midguts and associated fat bodies of unfed or fed adults. Quantitative (Real-Time) RT-PCR (qRT-PCR) experiments confirmed that the microarray data accurately reflect expression levels in the different samples. Candidate genes encoding enzymes involved in terminal steps of biosynthetic pathways for <it>exo</it>-brevicomin and frontalin were tentatively identified.</p> <p>Conclusions</p> <p>These EST and microarray data are the first publicly-available functional genomics resources for this devastating forestry pest.</p

Modelling gambiense human African trypanosomiasis infection in villages of the Democratic Republic of Congo using Kolmogorov forward equations

Stochastic methods for modelling disease dynamics enables the direct computation of the probability of elimination of transmission (EOT). For the low-prevalence disease of human African trypanosomiasis (gHAT), we develop a new mechanistic model for gHAT infection that determines the full probability distribution of the gHAT infection using Kolmogorov forward equations. The methodology allows the analytical investigation of the probabilities of gHAT elimination in the spatially-connected villages of different prevalence health zones of the Democratic Republic of Congo, and captures the uncertainty using exact methods. Our method provides a more realistic approach to scaling the probability of elimination of infection between single villages and much larger regions, and provides results comparable to established models without the requirement of detailed infection structure. The novel flexibility allows the interventions in the model to be implemented specific to each village, and this introduces the framework to consider the possible future strategies of test-and-treat or direct treatment of individuals living in villages where cases have been found, using a new drug

Cost-effectiveness modelling to optimise active screening strategy for gambiense human African trypanosomiasis in endemic areas of the Democratic Republic of Congo

Background: Gambiense human African trypanosomiasis (gHAT) has been brought under control recently with village-based active screening playing a major role in case reduction. In the approach to elimination, we investigate how to optimise active screening in villages in the Democratic Republic of Congo, such that the expenses of screening programmes can be efficiently allocated whilst continuing to avert morbidity and mortality. Methods: We implement a cost-effectiveness analysis using a stochastic gHAT infection model for a range of active screening strategies and, in conjunction with a cost model, we calculate the net monetary benefit (NMB) of each strategy. We focus on the high-endemicity health zone of Kwamouth in the Democratic Republic of Congo. Results: High-coverage active screening strategies, occurring approximately annually, attain the highest NMB. For realistic screening at 55% coverage, annual screening is cost-effective at very low willingness-to-pay thresholds (20.4 per disability adjusted life year (DALY) averted), only marginally higher than biennial screening (14.6 per DALY averted). We find that, for strategies stopping after 1, 2 or 3 years of zero case reporting, the expected cost-benefits are very similar. Conclusions: We highlight the current recommended strategy—annual screening with three years of zero case reporting before stopping active screening—is likely cost-effective, in addition to providing valuable information on whether transmission has been interrupted

Utility of repeat cytological assessment of thyroid nodules initially classified as benign: clinical insights from multidisciplinary care in an Irish tertiary referral centre.

BACKGROUND: Fine needle aspiration biopsy (FNAB) is the tool of choice for evaluating thyroid nodules with the majority classified as benign following initial assessment. However, concern remains about false negative results and some guidelines have recommended routine repeat aspirates. We aimed to assess the utility of routine repeat FNAB for nodules classified as benign on initial biopsy and to examine the impact of establishing a multidisciplinary team for the care of these patients. METHODS: We performed a retrospective review of 400 consecutive patients (413 nodules) who underwent FNAB of a thyroid nodule at our hospital between July 2008 and July 2011. Data recorded included demographic, clinical, histological and radiological variables. RESULTS: Three hundred and fifty seven patients (89 %) were female. Median follow-up was 5.5 years. Two hundred and fifty eight (63 %) nodules were diagnosed as benign. The rate of routine repeat biopsy increased significantly over the time course of the study (p for trend = 0.012). Nine Thy 2 nodules were classified differently on the basis of routine repeat biopsy; one patient was classified as malignant on repeat biopsy and was diagnosed with papillary thyroid carcinoma. Eight were classified as a follicular lesions on repeat biopsy-six diagnosed as benign following lobectomy; two declined lobectomy and were followed radiologically with no nodule size increase. CONCLUSIONS: The false negative rate of an initial benign cytology result, from a thyroid nodule aspirate, is low. In the setting of an experienced multidisciplinary thyroid team, routine repeat aspiration is not justified